-
ELife Sep 2023Interactions between an enzyme kinase, an ion channel and cytoskeletal proteins maintain the structure of synapses involved in memory formation.
Interactions between an enzyme kinase, an ion channel and cytoskeletal proteins maintain the structure of synapses involved in memory formation.
Topics: Dendritic Spines; Cytoskeletal Proteins
PubMed: 37676261
DOI: 10.7554/eLife.91566 -
Biological Psychiatry Aug 2021Diacylglycerol lipase α (DAGLα), a major biosynthetic enzyme for endogenous cannabinoid signaling, has emerged as a risk gene in multiple psychiatric disorders....
BACKGROUND
Diacylglycerol lipase α (DAGLα), a major biosynthetic enzyme for endogenous cannabinoid signaling, has emerged as a risk gene in multiple psychiatric disorders. However, its role in the regulation of dendritic spine plasticity is unclear.
METHODS
DAGLα wild-type or point mutants were overexpressed in primary cortical neurons or human embryonic kidney 293T cells. The effects of mutated variants on interaction, dendritic spine morphology, and dynamics were examined by proximity ligation assay or fluorescence recovery after photobleaching. Behavioral tests and immunohistochemistry were performed with ankyrin-G conditional knockout and wild-type male mice.
RESULTS
DAGLα modulated dendritic spine size and density, but the effects of changes in its protein level versus enzymatic activity were different, implicating either a 2-arachidonoylglycerol (2-AG)-dependent or -independent mechanism. The 2-AG-independent effects were mediated by the interaction of DAGLα with ankyrin-G, a multifunctional scaffold protein implicated in psychiatric disorders. Using superresolution microscopy, we observed that they colocalized in distinct nanodomains, which correlated with spine size. In situ proximity ligation assay combined with structured illumination microscopy revealed that DAGLα phosphorylation upon forskolin treatment enhanced the interaction with ankyrin-G in spines, leading to increased spine size and decreased DAGLα surface diffusion. Ankyrin-G conditional knockout mice showed significantly decreased DAGLα-positive neurons in the forebrain. In mice, ankyrin-G was required for forskolin-dependent reversal of depression-related behavior.
CONCLUSIONS
Taken together, ANK3 and DAGLA, both neuropsychiatric disorder genes, interact in a complex to regulate spine morphology. These data reveal novel synaptic signaling mechanisms and potential therapeutic avenues.
Topics: Animals; Ankyrins; Dendritic Spines; Humans; Lipoprotein Lipase; Male; Mice; Phosphorylation; Signal Transduction
PubMed: 34099188
DOI: 10.1016/j.biopsych.2021.03.023 -
EMBO Reports Aug 2012Dendritic spines arise as small protrusions from the dendritic shaft of various types of neuron and receive inputs from excitatory axons. Ever since dendritic spines... (Review)
Review
Dendritic spines arise as small protrusions from the dendritic shaft of various types of neuron and receive inputs from excitatory axons. Ever since dendritic spines were first described in the nineteenth century, questions about their function have spawned many hypotheses. In this review, we introduce understanding of the structural and biochemical properties of dendritic spines with emphasis on components studied with imaging methods. We then explore advances in in vivo imaging methods that are allowing spine activity to be studied in living tissue, from super-resolution techniques to calcium imaging. Finally, we review studies on spine structure and function in vivo. These new results shed light on the development, integration properties and plasticity of spines.
Topics: Dendritic Spines; Humans; Imaging, Three-Dimensional; Models, Biological; Neuronal Plasticity; Synaptic Transmission
PubMed: 22791026
DOI: 10.1038/embor.2012.102 -
Neuroscience Aug 2022Dendritic spines are small protrusions on dendrites that serve as the postsynaptic site of the majority of excitatory synapses. These structures are important for normal... (Comparative Study)
Comparative Study
Dendritic spines are small protrusions on dendrites that serve as the postsynaptic site of the majority of excitatory synapses. These structures are important for normal synaptic transmission, and alterations in their density and morphology have been documented in various disease states. Over 130 years ago, Ramón y Cajal used Golgi-stained tissue sections to study dendritic morphology. Despite the array of technological advances, including iontophoretic microinjection of Lucifer yellow (LY) fluorescent dye, Golgi staining continues to be one of the most popular approaches to visualize dendritic spines. Here, we compared dendritic spine density and morphology among pyramidal neurons in layers 2/3 of the mouse medial prefrontal cortex (mPFC) and pyramidal neurons in hippocampal CA1 using three-dimensional digital reconstructions of (1) brightfield microscopy z-stacks of Golgi-impregnated dendrites and (2) confocal microscopy z-stacks of LY-filled dendrites. Analysis of spine density revealed that the LY microinjection approach enabled detection of approximately three times as many spines as the Golgi staining approach in both brain regions. Spine volume measurements were larger using Golgi staining compared to LY microinjection in both mPFC and CA1. Spine length was mostly comparable between techniques in both regions. In the mPFC, head diameter was similar for Golgi staining and LY microinjection. However, in CA1, head diameter was approximately 50% smaller on LY-filled dendrites compared to Golgi staining. These results indicate that Golgi staining and LY microinjection yield different spine density and morphology measurements, with Golgi staining failing to detect dendritic spines and overestimating spine size.
Topics: Animals; Dendrites; Dendritic Spines; Hippocampus; Isoquinolines; Mice; Pyramidal Cells
PubMed: 35752428
DOI: 10.1016/j.neuroscience.2022.06.029 -
CNS Neuroscience & Therapeutics Aug 2023Functional recovery is associated with the preservation of dendritic spines in the penumbra area after stroke. Previous studies found that polymerized microtubules (MTs)...
BACKGROUND AND AIM
Functional recovery is associated with the preservation of dendritic spines in the penumbra area after stroke. Previous studies found that polymerized microtubules (MTs) serve a crucial role in regulating dendritic spine formation and plasticity. However, the mechanisms that are involved are poorly understood. This study is designed to understand whether the upregulation of acetylated α-tubulin (α-Ac-Tub, a marker for stable, and polymerized MTs) could alleviate injury to the dendritic spines in the penumbra area and motor dysfunction after ischemic stroke.
METHODS
Ischemic stroke was mimicked both in an in vivo and in vitro setup using middle cerebral artery occlusion and oxygen-glucose deprivation models. Thy1-YFP mice were utilized to observe the morphology of the dendritic spines in the penumbra area. MEC17 is the specific acetyltransferase of α-tubulin. Thy1 Cre and MEC17 mice were mated to produce mice with decreased expression of α-Ac-Tub in dendritic spines of pyramidal neurons in the cerebral cortex. Moreover, AAV-PHP.B-DIO-MEC17 virus and tubastatin A (TBA) were injected into Thy1 Cre and Thy1-YFP mice to increase α-Ac-Tub expression. Single-pellet retrieval, irregular ladder walking, rotarod, and cylinder tests were performed to test the motor function after the ischemic stroke.
RESULTS
α-Ac-Tub was colocalized with postsynaptic density 95. Although knockout of MEC17 in the pyramidal neurons did not affect the density of the dendritic spines, it significantly aggravated the injury to them in the penumbra area and motor dysfunction after stroke. However, MEC17 upregulation in the pyramidal neurons and TBA treatment could maintain mature dendritic spine density and alleviate motor dysfunction after stroke.
CONCLUSION
Our study demonstrated that α-Ac-Tub plays a crucial role in the maintenance of the structure and functions of mature dendritic spines. Moreover, α-Ac-Tub protected the dendritic spines in the penumbra area and alleviated motor dysfunction after stroke.
Topics: Mice; Animals; Dendritic Spines; Tubulin; Ischemic Stroke; Pyramidal Cells; Stroke
PubMed: 36965035
DOI: 10.1111/cns.14184 -
Hormones and Behavior Aug 2015This article is part of a Special Issue "Estradiol and Cognition". Memory processing is presumed to depend on synaptic plasticity, which appears to have a role in... (Review)
Review
This article is part of a Special Issue "Estradiol and Cognition". Memory processing is presumed to depend on synaptic plasticity, which appears to have a role in mediating the acquisition, consolidation, and retention of memory. We have studied the relationship between estrogen, recognition memory, and dendritic spine density in the hippocampus and medial prefrontal cortex, areas critical for memory, across the lifespan in female rodents. The present paper reviews the literature on dendritic spine plasticity in mediating both short and long term memory, as well as the decreased memory that occurs with aging and Alzheimer's disease. It also addresses the role of acute and chronic estrogen treatments in these processes.
Topics: Aging; Animals; Cognition; Dendritic Spines; Estradiol; Female; Hippocampus; Humans; Longevity; Memory; Neuronal Plasticity; Prefrontal Cortex
PubMed: 25993604
DOI: 10.1016/j.yhbeh.2015.05.004 -
Journal of Neurophysiology Jun 2016Neuropathic pain is a significant complication following spinal cord injury (SCI) with few effective treatments. Drug development for neuropathic pain often fails...
Neuropathic pain is a significant complication following spinal cord injury (SCI) with few effective treatments. Drug development for neuropathic pain often fails because preclinical studies do not always translate well to clinical conditions. Identification of biological characteristics predictive of disease state or drug responsiveness could facilitate more effective clinical translation. Emerging evidence indicates a strong correlation between dendritic spine dysgenesis and neuropathic pain. Because dendritic spines are located on dorsal horn neurons within the spinal cord nociceptive system, dendritic spine remodeling provides a unique opportunity to understand sensory dysfunction after SCI. In this study, we provide support for the postulate that dendritic spine profiles can serve as biomarkers for neuropathic pain. We show that dendritic spine profiles after SCI change to a dysgenic state that is characteristic of neuropathic pain in a Rac1-dependent manner. Suppression of the dysgenic state through inhibition of Rac1 activity is accompanied by attenuation of neuropathic pain. Both dendritic spine dysgenesis and neuropathic pain return when inhibition of Rac1 activity is lifted. These findings suggest the utility of dendritic spines as structural biomarkers for neuropathic pain.
Topics: Animals; Catheters, Indwelling; Dendritic Spines; Male; Microelectrodes; Neuralgia; Neuronal Plasticity; Posterior Horn Cells; Rats, Sprague-Dawley; Spinal Cord; Spinal Cord Injuries; Time Factors; Touch; rac1 GTP-Binding Protein
PubMed: 26936986
DOI: 10.1152/jn.01057.2015 -
Translational Psychiatry Dec 2018Stress is a major risk factor for the onset of many psychiatric diseases. In rodent models, chronic stress induces depression and impairs excitatory neurotransmission....
Stress is a major risk factor for the onset of many psychiatric diseases. In rodent models, chronic stress induces depression and impairs excitatory neurotransmission. However, little is known about the effect of stress on synaptic circuitry during the development of behavioral symptoms. Using two-photon transcranial imaging, we studied the effect of repeated restraint stress on dendritic spine plasticity in the frontal cortex in vivo. We found that restraint stress induced dendritic spine loss by decreasing the rate of spine formation and increasing the rate of spine elimination. The N-methyl-D-aspartate receptor antagonist ketamine inhibited stress-induced spine loss mainly by protecting mushroom spines from elimination. Ketamine also induced re-formation of spines in close proximity to previously stress-eliminated spines. Electrophysiological and in vivo imaging experiments showed that ketamine enhanced activity of parvalbumin (PV) interneurons under stress and counterbalanced the stress-induced net loss of PV axonal boutons. In addition, selective chemogenetic excitation of PV interneurons mimicked the protective effects of ketamine on dendritic spines against stress. Collectively, our data provide new insights on the effects of ketamine on synaptic circuitry under stress and a possible mechanism to counteract stress-induced synaptic impairments through PV interneuron activation.
Topics: Animals; Dendritic Spines; Excitatory Amino Acid Antagonists; Female; Frontal Lobe; Interneurons; Ketamine; Male; Mice, Inbred C57BL; Neuronal Plasticity; Parvalbumins; Restraint, Physical; Stress, Psychological
PubMed: 30531859
DOI: 10.1038/s41398-018-0321-5 -
Neuroscience Oct 2013Dendritic spines, the bulbous protrusions that form the postsynaptic half of excitatory synapses, are one of the most prominent features of neurons and have been imaged... (Review)
Review
Dendritic spines, the bulbous protrusions that form the postsynaptic half of excitatory synapses, are one of the most prominent features of neurons and have been imaged and studied for over a century. In that time, changes in the number and morphology of dendritic spines have been correlated to the developmental process as well as the pathophysiology of a number of neurodegenerative diseases. Due to the sheer scale of synaptic connectivity in the brain, work to date has merely scratched the surface in the study of normal spine function and pathology. This review will highlight traditional approaches to the imaging of dendritic spines and newer approaches made possible by advances in microscopy, protein engineering, and image analysis. The review will also describe recent work that is leading researchers toward the possibility of a systematic and comprehensive study of spine anatomy throughout the brain.
Topics: Dendritic Spines; Microscopy; Optical Imaging; Silver Staining
PubMed: 22522468
DOI: 10.1016/j.neuroscience.2012.04.010 -
PloS One 2014A current model posits that cofilin-dependent actin severing negatively impacts dendritic spine volume. Studies suggested that increased cofilin activity underlies...
A current model posits that cofilin-dependent actin severing negatively impacts dendritic spine volume. Studies suggested that increased cofilin activity underlies activity-dependent spine shrinkage, and that reduced cofilin activity induces activity-dependent spine growth. We suggest instead that both types of structural plasticity correlate with decreased cofilin activity. However, the mechanism of inhibition determines the outcome for spine morphology. RNAi in rat hippocampal cultures demonstrates that cofilin is essential for normal spine maintenance. Cofilin-F-actin binding and filament barbed-end production decrease during the early phase of activity-dependent spine shrinkage; cofilin concentration also decreases. Inhibition of the cathepsin B/L family of proteases prevents both cofilin loss and spine shrinkage. Conversely, during activity-dependent spine growth, LIM kinase stimulates cofilin phosphorylation, which activates phospholipase D-1 to promote actin polymerization. These results implicate novel molecular mechanisms and prompt a revision of the current model for how cofilin functions in activity-dependent structural plasticity.
Topics: Actins; Animals; Cells, Cultured; Cofilin 1; Dendritic Spines; Down-Regulation; Female; Hippocampus; Immunohistochemistry; Lim Kinases; Long-Term Potentiation; Long-Term Synaptic Depression; Microscopy, Confocal; N-Methylaspartate; Neurons; Phospholipase D; Phosphorylation; Protein Binding; RNA Interference; Rats; Tacrolimus; Time-Lapse Imaging
PubMed: 24740405
DOI: 10.1371/journal.pone.0094787